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Mortality and Paclitaxel-Coated Devices
Quick Takes
- Meta-analysis of patient-level data from eight RCTs of FDA-approved paclitaxel-coated balloons and stents versus balloon angioplasty observed 4.6% absolute risk of increased mortality associated with paclitaxel-coated devices at median 4-year follow-up.
- Loss to follow-up was significant (24% for balloon angioplasty and 23% for paclitaxel cohorts, respectively, at 5 years), and the mortality effect observed was attenuated after a National Death Index query recovered some of the missing vital status data.
- Study sponsors provided anonymized patient-level data, and the statistical analysis plan was developed by a four-member multispecialty data steering committee assembled by VIVA physicians with FDA guidance and industry member approval.
Study Questions:
Is use of paclitaxel-containing devices for treatment of symptomatic femoral-popliteal peripheral artery disease (PAD) associated with mortality?
Methods:
Data from four randomized, controlled trials (RCTs) evaluating paclitaxel-coated balloons and stents were anonymized and provided by sponsors. The analysis plan was developed by a four-member data steering committee assembled by VIVA physicians with advice from the Food and Drug Administration (FDA), and industry members had review and approval of the plan. Participants had femoral-popliteal PAD with symptoms of claudication and/or rest pain. Trial inclusion criteria included a minimum of 2-year follow-up and availability of individual patient-level data. The primary outcome, mortality, was evaluated using a Cox proportional hazards model stratified by study. An “as-treated” analysis adjusted for prespecified propensity score covariates was used to explore mortality differences between study arms and possible biases. Associations between paclitaxel dose and mortality were explored using standardized doses calculated from a proportional hazards model with stratification by study and propensity-score weighting.
Results:
Paclitaxel-coated devices were associated with increased risk for overall mortality versus control (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.06-1.80), indicating a 38% relative increase in mortality. Mortality through 5 years was 18.3% for paclitaxel-coated devices versus 13.7% for control, an absolute difference of 4.6%. Sensitivity analysis indicated that missing data had an impact, and additional vital status data obtained through direct clinical site queries and the National Death Index attenuated the mortality association to a 27% relative increase (HR, 1.27; 95% CI, 1.03-1.58). No association between mortality and drug dose was identified.
Conclusions:
An absolute 4.6% increased mortality risk associated with use of paclitaxel-coated devices was identified in this meta-analysis of individual patient data from randomized trials.
Perspective:
The association between paclitaxel-coated devices and mortality reported in the meta-analysis by Katsanos, et al. in 2018 precipitated a series of ongoing controversies related to the mechanism, generalizability, and how the findings should be applied to clinical management of PAD. The current study includes individual patient-level data from RCTs, overcoming a much-discussed limitation of the previous meta-analysis, and the results support an association between paclitaxel-containing devices and mortality.
The authors do a good job summarizing the challenges of evaluating patient-level outcomes using data from trials designed around lesion-specific outcomes with heterogeneous inclusion criteria, study designs, and data sources. The current study mitigates some of these issues by limiting the analysis to a specific anatomic distribution (femoral-popliteal) and a minimum follow-up (2 years) that permits detection of late mortality. In addition to the observed mortality effect, the importance of participant follow-up (and, conversely, lack thereof as an influential source of bias) is noteworthy and warrants consideration when evaluating this rapidly expanding body of literature.
The collaboration between a multispecialty physician organization, the US FDA, and industry exemplified by this study demonstrates the importance of this question to a number of stakeholders. Patients undergoing lower extremity revascularization that will potentially involve a paclitaxel-containing device have the most at stake, and it is time to get them more directly involved as partners in this effort. Understanding how patients evaluate tradeoffs between revascularization durability and mortality risk will be critical to inform decision making at both aggregate and individual levels, but will require novel approaches to treatment selection and clinician buy-in to succeed.
Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and Arrhythmias, Interventions and Vascular Medicine
Keywords: Angioplasty, Angioplasty, Balloon, Intermittent Claudication, Popliteal Artery, Femoral Artery, Myocardial Revascularization, Paclitaxel, Pain, Peripheral Arterial Disease, Risk, Secondary Prevention, Stents, Vascular Diseases
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